Abstract
Original language | English |
---|---|
Article number | 2779 |
Journal | Nature communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2023 |
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In: Nature communications, Vol. 14, No. 1, 2779, 01.12.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
AU - Costa-Machado, Luis Filipe
AU - Garcia-Dominguez, Esther
AU - McIntyre, Rebecca L.
AU - Lopez-Aceituno, Jose Luis
AU - Ballesteros-Gonzalez, Álvaro
AU - Tapia-Gonzalez, Andrea
AU - Fabregat-Safont, David
AU - Eisenberg, Tobias
AU - Gomez, Jesús
AU - Plaza, Adrian
AU - Sierra-Ramirez, Aranzazu
AU - Perez, Manuel
AU - Villanueva-Bermejo, David
AU - Fornari, Tiziana
AU - Loza, María Isabel
AU - Herradon, Gonzalo
AU - Hofer, Sebastian J.
AU - Magnes, Christoph
AU - Madeo, Frank
AU - Duerr, Janet S.
AU - Pozo, Oscar J.
AU - Galindo, Maximo-Ibo
AU - del Pino, Isabel
AU - Houtkooper, Riekelt H.
AU - Megias, Diego
AU - Viña, Jose
AU - Gomez-Cabrera, Mari Carmen
AU - Fernandez-Marcos, Pablo J.
N1 - Funding Information: We thank Manuel Serrano for his unfaltering support and advice; Fernando Pelaez, Isabel Blanco and Alejo Efeyan for their help in the CNIO facilities; Rosa Serrano and Concepcion Timon for their help with animal procedures; Marta Barradas for her help and support in the laboratory tasks; Laura Formentini and Jose Antonio Enriquez for their kind technical and scientific support; and the Caenorhabditis Genetics Center (CGC) at the University of Minnesota for providing C. elegans strains. L.F.C.-M. was supported by the IMDEA Food institute and by a PhD Fellowship from the Portuguese Foundation for Science and Technology (FCT‐MCTES, SFRH/BD/124022/2016). Work in the laboratory of P.J.F.-M. was funded by the IMDEA Food Institute, the Ramón Areces Foundation (CIVP18A3891), the AECC (SIRTBIO, LABAE18008FERN), the MICINN (SAF2017-85766-R and PRPPID2020-114077RB-I00) co-funded by the European Regional Development Fund, and a Ramon y Cajal Fellowship (MICINN, RYC-2017-22335). J.L.L.-A. was funded by the Spanish Ministry of Science and Innovation (MICINN) (PTA2017‐14689‐I). Work in FreshAge laboratory was funded by: Instituto de Salud Carlos III CB16/10/00435 (CIBERFES), (PID2019-110906RB-I00/AEI/10.13039/501100011033) from the Spanish Ministry of Innovation and Science; FGCSIC/PSLINTERREG/FEDER; PROMETEO/2019/097 de “Consellería de Sanitat de la Generalitat Valenciana” and EU Funded H2020- DIABFRAIL-LATAM (Ref: 825546). Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana). Support from Ramón Areces Fundation and Soria Melguizo Foundation is also acknowledged. E.G.-D. was a recipient of a predoctoral grant financed by the Spanish Ministry (FPU18/05350). Work in the laboratory of IdP was funded by the MICINN (RTI2018-100872-J-I00) and PlaGenT excellence research program of the Valencian regional government (CIDENGENT/2019/044). Work in the laboratory of M.-I.G. was funded by PROMETEU/2018/135 from “Consellería, de Sanitat de la Generalitat Valenciana” and part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014–2020). F.M. is grateful to the Austrian Science Fund FWF (SFB-LIPOTOX F3007 & F3012, W1226, P29203, P29262, P27893, and P31727); the Austrian Federal Ministry of Education, Science and Research and the University of Graz for grants Unkonventionelle Forschung-InterFast and ysleep (BMWFW-80.109/0001-WF/V/3b/2015) and the field of excellence program BioHealth. We acknowledge support from NAWI Graz, the BioTechMed-Graz agship project EPIAge. T.E. acknowledges support from Austrian Science Fund FWF (P 33957 and TAI 602 1000). Work in the laboratory of R.H.H. was financially supported by a VIDI grant from ZonMw (no. 91715305). J.S.D. was supported by Ohio University. D.F.-S. acknowledges Ministerio de Universidades in Spain for his Margarita Salas postdoctoral grant (Ref. MGS/2021/15). The CGC group is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Funding Information: We thank Manuel Serrano for his unfaltering support and advice; Fernando Pelaez, Isabel Blanco and Alejo Efeyan for their help in the CNIO facilities; Rosa Serrano and Concepcion Timon for their help with animal procedures; Marta Barradas for her help and support in the laboratory tasks; Laura Formentini and Jose Antonio Enriquez for their kind technical and scientific support; and the Caenorhabditis Genetics Center (CGC) at the University of Minnesota for providing C. elegans strains. L.F.C.-M. was supported by the IMDEA Food institute and by a PhD Fellowship from the Portuguese Foundation for Science and Technology (FCT‐MCTES, SFRH/BD/124022/2016). Work in the laboratory of P.J.F.-M. was funded by the IMDEA Food Institute, the Ramón Areces Foundation (CIVP18A3891), the AECC (SIRTBIO, LABAE18008FERN), the MICINN (SAF2017-85766-R and PRPPID2020-114077RB-I00) co-funded by the European Regional Development Fund, and a Ramon y Cajal Fellowship (MICINN, RYC-2017-22335). J.L.L.-A. was funded by the Spanish Ministry of Science and Innovation (MICINN) (PTA2017‐14689‐I). Work in FreshAge laboratory was funded by: Instituto de Salud Carlos III CB16/10/00435 (CIBERFES), (PID2019-110906RB-I00/AEI/10.13039/501100011033) from the Spanish Ministry of Innovation and Science; FGCSIC/PSLINTERREG/FEDER; PROMETEO/2019/097 de “Consellería de Sanitat de la Generalitat Valenciana” and EU Funded H2020- DIABFRAIL-LATAM (Ref: 825546). Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana). Support from Ramón Areces Fundation and Soria Melguizo Foundation is also acknowledged. E.G.-D. was a recipient of a predoctoral grant financed by the Spanish Ministry (FPU18/05350). Work in the laboratory of IdP was funded by the MICINN (RTI2018-100872-J-I00) and PlaGenT excellence research program of the Valencian regional government (CIDENGENT/2019/044). Work in the laboratory of M.-I.G. was funded by PROMETEU/2018/135 from “Consellería, de Sanitat de la Generalitat Valenciana” and part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014–2020). F.M. is grateful to the Austrian Science Fund FWF (SFB-LIPOTOX F3007 & F3012, W1226, P29203, P29262, P27893, and P31727); the Austrian Federal Ministry of Education, Science and Research and the University of Graz for grants Unkonventionelle Forschung-InterFast and ysleep (BMWFW-80.109/0001-WF/V/3b/2015) and the field of excellence program BioHealth. We acknowledge support from NAWI Graz, the BioTechMed-Graz agship project EPIAge. T.E. acknowledges support from Austrian Science Fund FWF (P 33957 and TAI 602 1000). Work in the laboratory of R.H.H. was financially supported by a VIDI grant from ZonMw (no. 91715305). J.S.D. was supported by Ohio University. D.F.-S. acknowledges Ministerio de Universidades in Spain for his Margarita Salas postdoctoral grant (Ref. MGS/2021/15). The CGC group is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood–brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.
AB - Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood–brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.
UR - http://www.scopus.com/inward/record.url?scp=85159274106&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-38410-y
DO - https://doi.org/10.1038/s41467-023-38410-y
M3 - Article
C2 - 37188705
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2779
ER -